Our goal is to define the molecular events that occur in the bronchopulmonary epithelium in the premalignant state. This involves mapping the expression of growth factors and their receptors, oncogenes and tumor suppressor genes at the cellular level in the progenitor cells of lung cancer in the non-neoplastic lung. This helps to understand the order of events leading to malignant transformation, and provides tools for early detection of cancer and cancer susceptible individuals as well as basis for the early intervention. Characterization of the system. Surgically resected pairs of malignant and corresponding non-neoplastic lung from the same patient composed of all NSCLC types was studied by RNA-RNA in situ hybridization for the expression of myc-family oncogenes and the peripheral airway cell (PAC) cell(progenitor cells) differentiation. c-Myc oncogene was overexpressed in 8 out of 17 tumors, 2 of which also expressed L-myc, while 15 out of 17 lungs showed low levels of c-myc both in airway epithelium and alveoli. N-myc levels both in tumors and lung tissue remained undetectable. The expression of PAC differentiation genes SP-a (the major surfactant associated protein) and Clara cell protein was focal in 4 tumors and restricted to type II cells in alveoli and bronchiolar cells of the lung, respectively. By immunohistochemistry 5 tumors were positive for p53 staining signifying the possible presence of mutated form of this suppressor gene. These results suggest that 1) expression of myc in NSCLC is a common event and 2) low levels are present in most cells in the lung and 3) PAC differentiation is restricted to subpopulations of bronchopulmonary cells.